fMRI differences in encoding and retrieval of pictures due to encoding strategy in the elderly

Functional MRI (fMRI) was used to examine the neural correlates of depth of processing during encoding and retrieval of photographs in older normal volunteers (n = 12). Separate scans were run during deep (natural vs. man-made decision) and shallow (color vs. black-and-white decision) encoding and during old/new recognition of pictures initially presented in one of the two encoding conditions. A baseline condition consisting of a scrambled, color photograph was used as a contrast in each scan. Recognition accuracy was greater for the pictures on which semantic decisions were made at encoding, consistent with the expected levels of processing effect. A mixed-effects model was used to compare fMRI differences between conditions (deep-baseline vs. shallow-baseline) in both encoding and retrieval. For encoding, this contrast revealed greater activation associated with deep encoding in several areas, including the left parahippocampal gyrus (PHG), left middle temporal gyrus, and left anterior thalamus. Increased left hippocampal, right dorsolateral, and inferior frontal activations were found for recognition of items that had been presented in the deep relative to the shallow encoding condition. We speculate that the modulation of activity in these regions by the depth of processing manipulation shows that these regions support effective encoding and successful retrieval. A direct comparison between encoding and retrieval revealed greater activation during retrieval in the medial temporal (right hippocampus and bilateral PHG), anterior cingulate, and bilateral prefrontal (inferior and dorsolateral). Most notably, greater right posterior PHG was found during encoding compared to recognition. Focusing on the medial temporal lobe (MTL) region, our results suggest a greater involvement of both anterior MTL and prefrontal regions in retrieval compared to encoding.     

Reorganization of verbal and nonverbal memory in temporal lobe epilepsy due to unilateral hippocampal sclerosis

PURPOSE: Patients with temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) often suffer from material-specific memory impairments. The purpose of this study was to use functional magnetic resonance imaging (fMRI) to study the organization of specific memory functions in these patients. METHODS: We report 14 patients with unilateral TLE and HS, and 10 controls, performing an fMRI memory paradigm of word, picture, and face encoding. RESULTS: Compared with controls, patients with left TLE demonstrated less left MTL and greater right MTL activation and patients with right TLE demonstrated less right MTL and greater left MTL activation. Correlations between fMRI activation and memory performance revealed greater activation in the damaged left hippocampus to be correlated with better verbal memory performance in left TLE patients and greater right hippocampal activation to be correlated with better nonverbal memory in right TLE patients. Conversely, greater fMRI activation in the contralateral hippocampus correlated with worse memory performance. CONCLUSIONS: Our findings suggest that memory function in unilateral TLE is better when it is sustained by activation within the damaged hippocampus and that reorganization to the undamaged MTL is an inefficient process, incapable of preserving memory function.     

Relating medial temporal lobe volume to frontal fMRI activation for memory encoding in older adults

Neuroimaging research on the brain basis of memory decline in older adults typically has examined age-related changes either in structure or in function. Structural imaging studies have found that smaller medial temporal lobe (MTL) volumes are associated with lower memory performance. Functional imaging studies have found that older adults often exhibit bilateral frontal-lobe activation under conditions where young adults exhibit unilateral frontal activation. As yet, no one has examined whether these MTL structural and frontal-lobe functional findings are associated. In this study, we tested whether these findings were correlated in a population of healthy older adults in whom we previously demonstrated verbal memory performance was positively associated with left entorhinal cortex volume in the MTL (Rosen et al., 2003) and right frontal lobe activation during memory encoding (Rosen et al., 2002). Thirteen, non-demented, community-dwelling older adults participated both in a functional MRI (fMRI) study of verbal memory encoding and structural imaging. MRI-derived left entorhinal volume was measured on structural images and entered as a regressor against fMRI activation during verbal memory encoding. Right frontal activation (Brodmann's Area 47/insula) was positively correlated with left entorhinal cortex volume. These findings indicate a positive association between MTL volume and right frontal-lobe function that may underlie variability in memory performance among the elderly, and also suggest a two-stage model of memory decline in aging.     

fMRI memory assessment in healthy subjects: a new approach to view lateralization data at an individual level

We present a comprehensive and clinically applicable fMRI test—including both a verbal and a visuospatial task—for assessment of hemispheric specific memory in the medial temporal lobe (MTL). fMRI data was collected from 15 healthy right-handed volunteers. Whole-brain activation was analyzed as well as activation in two regions of interest: the MTL and the anterior speech area. Laterality indices (LI) and LI-curves were calculated using the LI toolbox of Wilke and Lidzba, 2007. The fMRI paradigms successfully visualized memory-related activity in the MTL, the verbal memory measure also provided information of language lateralization. Eleven subjects showed left lateralized verbal encoding in the MTL, visuospatial memory activation was divided equally between left and right, and 14/15 subjects had left lateralized language. Lateralization data at the group level were consistent with previous studies, but a variety of activation effects were found at the individual level indicating differences in strategy during verbal and visuospatial processing. Further studies using the presented method are needed to determine its clinical usefulness.     

The parahippocampal gyrus links the default‐mode cortical network with the medial temporal lobe memory system

The default‐mode network (DMN) is a distributed functional‐anatomic network implicated in supporting memory. Current resting‐state functional connectivity studies in humans remain divided on the exact involvement of medial temporal lobe (MTL) in this network at rest. Notably, it is unclear to what extent the MTL regions involved in successful memory encoding are connected to the cortical nodes of the DMN during resting state. Our findings using functional connectivity MRI analyses of resting‐state data indicate that the parahippocampal gyrus (PHG) is the primary hub of the DMN in the MTL during resting state. Also, connectivity of the PHG is distinct from connectivity of hippocampal regions identified by an associative memory‐encoding task. We confirmed that several hippocampal encoding regions lack significant functional connectivity with cortical DMN nodes during resting state. Additionally, a mediation analysis showed that resting‐state connectivity between the hippocampus and posterior cingulate cortex—a major hub of the DMN—is indirect and mediated by the PHG. Our findings support the hypothesis that the MTL memory system represents a functional subnetwork that relates to the cortical nodes of the DMN through parahippocampal functional connections. Hum Brain Mapp 35:1061–1073, 2014. © 2013 Wiley Periodicals, Inc.     

Adaptive visual memory reorganization in right medial temporal lobe epilepsy

Purpose: We investigated functional reorganization mechanisms of the human medial temporal lobe (MTL) for episodic memory, in patients suffering from medial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS).
Methods: We used functional magnetic resonance imaging (fMRI) to measure brain activity changes during matched episodic encoding tasks of abstract words (Verbal) and line drawings (Visual), in patients with unilateral right MTLE undergoing presurgical evaluation and healthy controls.
Results: As expected, a significant interaction between material type and the side of MTL activity was present in the control group, with preferential involvement of the left hippocampus in verbal encoding and the right parahippocampal region in visual encoding. When compared with controls, right MTLE patients with intact performance activated a region in the left hippocampus more during visual encoding, which resulted in an interaction between group and hemisphere. Importantly, an effect of memory performance on visual encoding activity was observed in the patients, with greater engagement of the left MTL being associated with higher recognition scores. Interestingly, activity in the left MTL also depended on the epileptic seizure frequency, suggesting a role for this clinical parameter in the recruitment of contralateral regions.
Discussion: Taken together, these results indicate functional reorganization of the MTLs in right HS, through transfer of function from the right to the left hemisphere, and strongly suggest an adaptive role for such reorganization mechanism in supporting preserved visual memory.     

Memory lateralization in medial temporal lobe epilepsy assessed by functional MRI

PURPOSE: To determine the utility of functional magnetic resonance imaging (fMRI) in preoperative lateralization of memory function in patients with medial temporal lobe epilepsy (MTLE). METHODS: Nine patients with MTLE underwent standard preoperative assessment including video-EEG and intracarotid amytal testing (IAT). fMRI was performed while subjects encoded four types of stimuli (patterns, faces, scenes, and words). Activation maps were created for each subject representing areas more active for novel than for repeated stimuli. Regions of interest were drawn around the MTL in individual subjects, suprathreshold voxels were counted, and an asymmetry index was calculated. RESULTS: In eight of nine subjects, lateralization of memory encoding by fMRI was concordant with that obtained from the IAT. Group-level analysis demonstrated greater activation in the MTL contralateral to the seizure focus such that in the left MTLE group, verbal encoding engaged the right MTL, whereas in the right MTLE group, nonverbal encoding engaged the left MTL. CONCLUSIONS: fMRI is a valid tool for assessing of memory lateralization in patients with MTLE and may therefore allow noninvasive preoperative evaluation of memory lateralization. FMRI revealed that memory encoding may be reorganized to the contralateral MTL in patients with MTLE.     

Entorhinal cortex volume is associated with episodic memory related brain activation in normal aging and amnesic mild cognitive impairment

The present study examined the relationship between entorhinal cortex and hippocampal volume with fMRI activation during episodic memory function in elderly controls with no cognitive impairment and individuals with amnesic mild cognitive impairment (aMCI). Both groups displayed limited evidence for a relationship between hippocampal volume and fMRI activation. Smaller right entorhinal cortex volume was correlated with reduced activation in left and right medial frontal cortex (BA 8) during incidental encoding for both aMCI and elderly controls. However, during recognition, smaller left entorhinal cortex volume correlated with reduced activation in right BA 8 for the control group, but greater activation for the aMCI group. There was no significant relationship between entorhinal cortex volume and activation during intentional encoding in either group. The recognition-related dissociation in structure/function relationships in aMCI paralleled our behavioral findings, where individuals with aMCI displayed poorer performance relative to controls during recognition, but not encoding. Taken together, these results suggest that the relationship between entorhinal cortex volume and fMRI activation during episodic memory function is altered in individuals with aMCI.     

Network interactions explain effective encoding in the context of medial temporal damage in MCI

Selective dysfunction in the medial temporal lobe (MTL) in amnestic mild cognitive impairment (MCI) results in a relatively circumscribed impairment in episodic memory. Previously, we found that activation extent in MTL during encoding correlated with subsequent recognition (hit rate) in controls but not in MCI patients (Mandzia et al. [2009]: Neurobiol Aging 30:717–730). Here, we examined whether functional connectivity amongst MTL and cortical regions might better explain differences in subsequent recognition success. Participants underwent fMRI scanning during picture encoding, and multivariate analysis was used to characterize the relationship between network activations and recognition. Both patients and controls activated a canonical MTL encoding network. However, this network correlated with hit rate only for controls. In MCI patients, recognition variability was best explained by the engagement of an additional network including BA 20. We propose that this pattern represents functional reorganization caused by reduced efficiency in the MTL network. Our findings suggest that understanding brain‐behavior relationships in neurological disorders requires examination of large‐scale networks, even when dysfunction is relatively focal as in MCI. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Brain activation on fMRI and verbal memory ability: functional neuroanatomic correlates of CVLT performance.

We have recently reported (Saykin et al., 1999b) selective activation of left medial temporal lobe structures during processing of novel compared to familiar words using functional magnetic resonance imaging (fMRI). The current study describes the relationship between a widely used clinical test of verbal learning, the California Verbal Learning Test (CVLT), and the previously reported fMRI activations. Thirteen right-handed healthy adult participants were studied with whole brain echo-planar fMRI while listening to novel and recently learned (familiar) words intermixed pseudorandomly in an event-related design. These participants were also tested with the CVLT. Scores for CVLT Trial 1 (immediate encoding of novel words) and recognition discriminability (recognition of familiar vs. novel words) were correlated with fMRI signal change during processing of novel versus familiar words using a covariance model implemented in SPM96. For the novel words analysis, voxels in the right anterior hippocampus correlated significantly with Trial 1 (r = .76 at the maxima). For the recognition analysis, a significant cluster of voxels was found in the right dorsolateral prefrontal cortex (r = .88 at the maxima). Our prior results of separable left medial temporal activation to novel and familiar words, together with results of the covariance analyses reported here, suggest that in addition to the left medial temporal lobe (MTL) regions that are engaged during novel and familiar word processing, the right hippocampus and right frontal lobe are also involved, particularly in those participants with better memory ability. This positive relationship between fMRI activation and CVLT performance suggests a role for these right hemisphere regions in successful memory processing of verbal material, perhaps reflecting more efficient encoding and retrieval strategies that facilitate memory.     

A Meta‐Analysis of fMRI Activation Differences during Episodic Memory in Alzheimer's Disease and Mild Cognitive Impairment

Functional MRI (fMRI) has the potential to be used as a tool to detect biomarkers related to classifying Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI). Previous meta‐analyses suggest that during episodic memory tasks, MCI patients exhibit hyperactivation in the medial temporal lobe (MTL) while AD patients exhibit hypoactivation, compared to healthy older adults (HOAs). However, these previous studies have methodological weaknesses that limit the generalizability of the results. This quantitative meta‐analysis re‐examines the activation associated with episodic memory in AD and MCI as compared to cognitively normal populations to assess these commonly cited activation differences. A whole‐brain activation likelihood estimation based meta‐analysis was conducted on fMRI studies that examined episodic memory in HOA (n = 200), MCI (n = 131), and AD populations (n = 89; total n = 409). Diffuse activation was exhibited in the HOA sample, while activation was more limited in the clinical populations. Additionally, the HOA sample showed more activation in the right hippocampus compared to the AD sample. The MCI studies showed greater activation in the cerebellum compared to the HOA sample, potentially indicating a compensatory mechanism for verbal encoding. MTL hypoactivation in the AD sample is consistent with previous studies, but more evidence of MCI hyperactivation is needed before considering MTL activation as an early biomarker for the AD disease process.     

Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: insights from functional MRI studies

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.     

Compensatory brain activation for recognition memory in patients with medication-resistant epilepsy

Progressive decline of memory functions has been observed in patients with chronic medication-resistant epilepsy. The progression likely relates to the effects of epileptiform discharges, seizures, and medications on the processes of encoding and retrieval. The goal of the study described here was to use functional MRI (fMRI) to examine the effects of chronic epilepsy on verbal recognition memory. We enrolled 12 patients with medication-resistant epilepsy (5 with right and 7 with left hemispheric seizure onset) and 18 healthy controls matched for age, gender, and handedness. Subjects underwent fMRI at 3T using a word recognition task during which they had to recall if words presented during scanning were words they had learned prior to scanning. Although we noted many similarities in the fMRI activation patterns between the subjects with epilepsy and the healthy subjects in areas typically involved in memory processing, testing of the interaction effects for target-foil differences between groups revealed several differences in activation including the right insula, the left cuneus, and the bilateral subgenual anterior cingulate cortex (ACC). In patients with epilepsy, these regions exhibited greater activation for targets than foils, but in healthy subjects the difference was reversed (right insula), absent (left cuneus), or included deactivation to target words (pregenual ACC). These differences were seen despite similar performance during the memory task, suggesting that activations observed in these additional regions may represent compensatory processes for verbal recognition memory that are induced by chronic brain injury related to recurrent seizures.     

Elaborative verbal encoding and altered anterior parahippocampal activation in adolescents and young adults at genetic risk for schizophrenia using FMRI.

BACKGROUND: First-degree relatives of persons with schizophrenia are at elevated risk for the illness, demonstrate deficits in verbal memory, and exhibit structural abnormalities in the medial temporal lobe (MTL). We used functional magnetic resonance imaging (fMRI) to assess brain activity in the MTL during novel and repeated word-pair encoding. METHODS: Participants were 21 non-psychotic, first-degree relatives of persons with schizophrenia and 26 matched healthy controls (ages 13-28). fMRI signal change was measured using a Siemens 1.5T MR scanner, and data were analyzed using SPM-2. Verbal memory was assessed using the Miller Selfridge (MS) Context Memory test prior to scanning. RESULTS: The groups were comparable on demographics, intelligence and post-scan word recognition. Relatives at genetic risk (GR) had significantly more psychopathology than controls and worse performance on the MS test (p < .05). GR participants exhibited greater repetition suppression of activation in the left and right anterior parahippocampus (PHA, in the region of the entorhinal cortex region), after controlling for possible confounders. Controls and GR participants with above-median MS performance showed significantly greater repetition suppression of activation in left inferior frontal gyrus than those scoring below the median. CONCLUSIONS: This is the first study to demonstrate an alteration of brain activity in the PHA in persons at GR for schizophrenia.     

Memory‐Related Hippocampal Activity Can Be Measured Robustly Using fMRI at 7 Tesla

High field strength functional magnetic resonance imaging (fMRI) has developed rapidly. However, it suffers from increased artifacts in brain regions such as the medial temporal lobe (MTL), challenging functional imaging of the hippocampus with the objective of high‐spatial resolution, which is particularly useful for this region both from a clinical and cognitive neuroscience perspective. We set out to compare a BOLD sequence at 7 T versus 3 T to visualize the MTL activity during an associative memory‐encoding task. Twenty‐eight healthy volunteers underwent a blocked‐design fMRI at either 3 T or 7 T while performing a face‐profession associative memory encoding task. Qualitative analyses of overall image quality revealed that functional images at 7 T were of high quality, showing a good white/gray matter contrast, with reasonably acceptable signal dropouts and artifacts at the lower portion of the temporal lobe. Analyses of task‐related fMRI data revealed robust activations in the bilateral MTL during associative memory encoding at both field strengths. Notably, we observed significantly stronger memory‐related hippocampal activation at 7 T than at 3 T, suggesting higher BOLD sensitivity at 7 T. These results are discussed in the light of the feasibility of 7 T scanning protocols for the MTL.     

Medial temporal lobe activation during encoding and retrieval of novel face-name pairs

The human medial temporal lobe (MTL) is known to be involved in declarative memory, yet the exact contributions of the various MTL structures are not well understood. In particular, the data as to whether the hippocampal region is preferentially involved in the encoding and/or retrieval of associative memory have not allowed for a consensus concerning its specific role. To investigate the role of the hippocampal region and the nearby MTL cortical areas in encoding and retrieval of associative versus non-associative memories, we used functional magnetic resonance imaging (fMRI) to measure brain activity during learning and later recognition testing of novel face-name pairs. We show that there is greater activity for successful encoding of associative information than for non-associative information in the right hippocampal region, as well as in the left amygdala and right parahippocampal cortex. Activity for retrieval of associative information was greater than for non-associative information in the right hippocampal region also, as well as in the left perirhinal cortex, right entorhinal cortex, and right parahippocampal cortex. The implications of these data for a clear functional distinction between the hippocampal region and the MTL cortical structures are discussed.     

Distinct functional activity of the precuneus and posterior cingulate cortex during encoding in the preclinical stage of Alzheimer's disease

In this study functional magnetic resonance imaging (fMRI) is used to investigate the functional brain activation pattern in the preclinical stage of AD (pre-AD) subjects during a visual encoding memory task. Thirty subjects, eleven in the pre-AD stage, with decreased cerebrospinal fluid levels of Aβ42 (<500 pg/ml), and 19 controls with normal Aβ42 levels (CTR) were included. fMRI was acquired during a visual encoding task. Data were analyzed through an Independent Component Analysis (ICA) and region-of-interest-based univariate analysis of task-related BOLD signal change. From the ICA decomposition, we identified the main task-related component, which included the activation of visual associative areas and prefrontal executive regions, and the deactivation of the default-mode network. The activation was positively correlated with task performance in the CTR group (p < 0.0054). Within this pattern, subjects in the pre-AD stage had significantly greater activation of the precuneus and posterior cingulate cortex during encoding. Subjects in the pre-AD stage present distinct functional neural activity before the appearance of clinical symptomatology. These findings may represent that subtle changes in functional brain activity precede clinical and cognitive symptoms in the AD continuum. Present findings provide evidence suggesting that fMRI may be a suitable biomarker of preclinical AD.     

Cerebral activation patterns during working memory performance in multiple sclerosis using FMRI

Working memory deficits are common in Multi Sclerosis (MS) and have been identified behaviourally in numerous studies. Despite recent advance in functional magnetic resonance imaging (fMRI), few published studies have examined cerebral activations associated with working memory dysfunction in MS. The present study examines brain activation patterns during performance of a working memory task in individual with clinically definite MS, compared to healthy controls (HC). fMRI was performed using a 1.5 Tesla GE scanner during a modified Paced Auditory Serial Addition Test (mPA-SAT). Participants were 6 individuals with MS with working memory impairment as evidenced on neuropsychological testing, 5 individuals with MS without working memory impairment, and 5 HC. Groups were demographically equivalent. Data were analyzed using Statistical Parametric Mapping (SPM99) software, with a stringent significance level (alpha < .005, voxel extent > or =8). Both MS groups and the HC group were able to perform the task, with comparable performance in terms of numbers of correct responses. Activation patterns within the HC and MS not-impaired groups were noted in similar brain regions, consistent with published observations in healthy samples That is, activations were lateralized to the left hemisphere, involving predominantly frontal regions. In contrast, the MS impaired group showed greater right frontal and right parietal lobe activation, when compared with the HC group. Thus, it appears that working memory dysfunction in MS is associated with altered patterns of cerebral activation that are related to the presence of cognitive impairement, and not solely a function of MS.     

Increased cerebral activation after behavioral treatment for memory deficits in MS

Deficits in new learning and memory are common in persons with multiple sclerosis (MS), though few studies have examined the efficacy of memory retraining in MS. Previous research from our laboratory has demonstrated that the modified Story Memory Technique (mSMT) significantly improves new learning and memory in MS. The present double-blind, placebo-controlled, randomized clinical trial was designed to examine changes in cerebral activation following mSMT treatment. Sixteen individuals with clinically definite MS were randomly assigned to treatment (n = 8) or placebo-control (n = 8) groups, matched for age, education, and disease characteristics. Baseline and follow-up fMRI was collected during performance of learning and memory tasks. No baseline activation differences on fMRI were seen between groups. After treatment, greater activation was evident in the treatment group during performance of a memory task within a widespread cortical network involving frontal, parietal, precuneus, and parahippocampal regions. All participants in the treatment group showed increased activation in frontal and temporal regions in particular. In contrast, the control group showed no significant changes in cerebral activation at follow-up. A significant association was found between increased activation in the right middle frontal gyrus and improved memory performance post-treatment. The increased activation seen likely reflects increased use of strategies taught during treatment when learning new information. This study is the first to demonstrate a significant change in cerebral activation resulting from a behavioral memory intervention in an MS sample. Behavioral interventions can show significant changes in the brain, validating clinical utility.     

Functional Alterations in Memory Networks in Early Alzheimer’s Disease

The hallmark clinical symptom of early Alzheimer’s disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD.